Yersinia pestis is the causative agent of disease in a variety of mammals, and humans can become infected when human and animal ecologies intersect. This has led to several pandemics of plague in human history, and infection with Y. pestis is currently considered by the WHO as a re-emerging infectious disease because of the increased incidence in a wide number of countries. Bubonic plague (transmitted via flea bite) is the most common form of disease and the untreated mortality rate is estimated at 40-70%. Mice are a natural host for Y. pestis and have long been used to study interactions of Y. pestis with a mammal during its normal cycle. Advantages of this are that we can use fully virulent bacteria and small inocula; furthermore, Y. pestis is genetically tractable allowing detailed analyses. These features are useful for gaining a fuller understanding of Y. pestis-host interactions, and it also make Y. pestis a useful and very sensitive model for understanding the hurdles an arthropod borne pathogen needs to overcome. We recently refined an intradermal infection model (to better mimic inoculation via a flea) and also developed a dissemination assay that allows us to monitor population dynamics at very early time points. Our recent results indicate there is a strong bottleneck between the inoculation site and establishment of infection in the draining lymph node (dLN), that neutrophils are not needed either for trafficking to the dLN or for the bottleneck, and that the bacteria can disseminate as free bacteria in the lymphatics. These observations lead to the hypothesis that specific bacterial determinants are not required for trafficking to the dLN but are required for establishing infection in the dLN and/or dissemination from the dLN to systemic sites. Our long-term goal is to understand the early events ultimately leading to a successful systemic infection and transmission to a new host. Specifically we propose to determine how known virulence factors affect specific steps between the inoculation site and blood, and how key host cells affect the development of pathology and systemic colonization. Together these studies will give us a clearer picture of how host-pathogen interactions and specific virulence determinants affect development of bubonic plague, providing a foundation for development of intervention strategies.